Perivascular Mesenchymal Cells Control Adipose Tissue Macrophage Accrual in Obesity

Chronic low-grade visceral white adipose tissue (WAT) inflammation is a hallmark of metabolic syndrome in obesity. Here, we demonstrate that a subpopulation of adipose tissue perivascular (PDGFRb+) cells, termed “fibro-inflammatory progenitors” (FIPs), activate pro-inflammatory signaling cascades shortly after the onset of high-fat diet feeding of mice and regulate pro-inflammatory macrophage accumulation in WAT in a TLR4-dependent manner. FIPs activation in obesity is mediated by the downregulation of ZFP423, identified here as a transcriptional co-regulator of NFkB. Biochemical analysis of ZFP423-protein complexes and ChIP-seq analysis reveal that ZFP423 suppresses the DNA-binding capacity of the p65 subunit of NFkB by inducing a p300 to NuRD co-regulator switch. Doxycycline-inducible expression of Zfp423 in PDGFRb+ cells suppresses inflammatory signaling in FIPs and attenuates metabolic inflammation of visceral WAT in obesity. Inducible inactivation of Zfp423 in PDGFRb+ cells increases FIP activity, exacerbates adipose macrophage accrual, and promotes WAT dysfunction. These studies implicate perivascular mesenchymal cells as important regulators of chronic adipose tissue inflammation in obesity and identify ZFP423 as a transcriptional break on NFkB signaling. Overall design: Bulk RNA-seq experiment to analyze gene expression profile in FIPs and APCs of gonadal white adipose tissue of Mural-Zfp423TG mice and Control animals under HFD feeding.